The mammalian brain is a complex and delicate organ which must operate within a highly secured environment. Not only is it sheltered from outside forces by the skull, but there is also an effective vascular protection system made of tightly wedged cells which make up the blood-brain barrier (BBB). The BBB was first characterized in 1885, when Paul Ehrlich injected dyes into live animals and observed that the brain was not stained blue like the rest of the body. The BBB protects the brain from pathogens, toxins and other insults, but represents a major obstacle to the delivery of drugs to the central nervous system (CNS). The BBB includes a vascular barrier (primarily capillary beds) and a blood-cerebrospinal fluid barrier (the choroid plexus), both of which are formed with a monolayer of endothelial cells cemented together by high-resistance intercellular tight junctions. Tight junctions seal the cells together so compounds and molecules must go through, rather than around, the endothelial cells. Tight junctions also restrict permeability between adjacent endothelial cells via polarized membrane proteins such as nutrient transporters. The BBB thus acts as a continuous blockade, preventing access of most blood-borne molecules, and only allowing entry of essential chemicals vital for CNS function.
Transport across the BBB typically occurs by one of the following means: lipid-mediated diffusion (lipophilic molecules only), carrier-mediated transport, receptor-mediated transcytosis, absorptive-mediated transcytosis or active transport. Although small, lipid-soluble agents can cross the BBB via diffusion through the capillary endothelial cells, they must have a sufficient amount of lipid solubility. Polar, water-soluble molecules enter the brain almost exclusively by carrier-mediated transport. Thus glucose, essential amino acids, glutamate, and most peptides (such as the naturally occurring enkephalins) which are polar and hydrophilic can only cross the BBB because a specific transport system is in place. If there is no such carrier, the BBB is a barrier that can be impossible to cross. Barrier permittivity of the BBB involves the surface activity of the molecule of interest, such as its hydrophobic and charged residues, as well as its relative size. The influence of the size of a compound or molecule on BBB penetration is generally inversely related to the square root of its molecular weight. In addition, the larger a compound is, the more difficult diffusion/entry will be no matter how beneficial its solubility characteristics are.
While physical properties such as low molecular weight and high lipid solubility both favor crossing the BBB by diffusion, passage through the BBB does not ensure that a compound will be pharmacologically effective. After passing through the monolayer of endothelial cells forming the BBB, the compound must then partition into the aqueous environment of the brain's interstitial fluid to exert an effect. As a result, a compound or molecule that is too lipid soluble can be sequestered by the capillary bed and not reach the cells behind the BBB. Lipid solubility also favors uptake by the peripheral tissues, which in turn lowers the concentration of the drug in blood. Thus, while the high lipid solubility of a specific compound can increase transport success across the BBB, it can also lower the amount of the compound presented to the brain. Even if the compound does manage to cross the BBB it may not arrive in a therapeutically relevant concentration, rendering it ineffective. Use of lipid solubility to improve drug delivery to the brain must thus find a balance between increased transport across the BBB and decreased amounts reaching the target tissue.
Additionally, the BBB is metabolically active and includes efflux transporters and enzymatic processes which play a large contributing role in final drug distribution. Several efflux transporters, such as the transmembrane protein P-glycoprotein (PGP), breast cancer resistance protein (BCRP), and multidrug resistance proteins (MRP) have profound clinical relevance to several CNS diseases such as cancers and HIV. Serving as a further defense to protect the brain, efflux transporter proteins can actively remove certain compounds or molecules that breach the BBB or they can deconstruct a compound or drug, making it inactive and rendering it useless.
In light of the above discussion, it is apparent that many hurdles must be overcome to successfully and effectively deliver a compound to the brain. A proposed treatment compound or molecule must be able to both cross the BBB and have a therapeutic effect within the brain. As a result, it is difficult to predict which compounds will penetrate the BBB to provide a therapeutic effect, and which will not. Most current brain-targeting therapies employ molecules that are either small enough or lipid-soluble enough to slip through the BBB in pharmacologically significant amounts. Further, attempts have been made to mimic lipid solubility. For example, U.S. Pat. No. 5,624,894 to Bodor describes placing a pharmacologically active peptide in a molecular environment which disguises its peptide nature by cloaking the polar ends of the peptide with lipophilic groups. The “lipidized” peptide is permitted unimpeded passive diffusion through the blood-brain barrier and into the brain capillaries. Several peptides have been successfully transported across the BBB that do not naturally show satisfactory BBB penetration, including two analgesics (a leucine-enkephalin analogue and kyotophin, an endogenous dipeptide) as well as a thyrotropin-releasing hormone analogue, which has potential applications for Alzheimer's disease and spinal cord injuries.
A number of approaches have been tried to overcome the challenges associated with drug delivery across the BBB, including disruption of the BBB, permeating the BBB, bypassing the BBB, or a combination thereof. Osmotic (e.g. using mannitol) and/or ultrasonic treatments can be used to temporarily disrupt the BBB, and many attempts have been made to utilize endogenous carrier proteins or synthetic “Trojan horses” (such as short amino acid chains or peptides) to “smuggle” drugs across the BBB. The BBB may be avoided entirely by direct injection of drugs into cerebrospinal fluid or directly into the brain. However, these methods present their own challenges such as ion imbalances, leaking neurotransmitters and release into the general circulation. While specific treatment regimens have benefitted from various measures devised to bypass the BBB, for many CNS treatment regimens the search for adequate brain delivery of a specific therapeutic compound or medicine continues. To date there is no unique vector that can be used as a universal brain delivery system.
Cannabis plants produce a group of biologically active chemicals called cannabinoids, which can produce mental and physical effects when consumed. A unique aspect of the BBB is that it allows cannabinoids to readily penetrate the BBB and bind with the brain's transmembrane cannabinoid receptors, CB1 and CB2. CB1 is particularly abundant in the brain, while CB2 is mainly expressed peripherally in the immune system. Cannabinoids mimic the action of anandamide, a naturally-occurring neurotransmitter. Anandamide is synthesized in areas of the brain controlling memory, motivation, higher thought processes, and movement control, and can affect one's appetite and reaction to pain. It may also help stop cancer cell proliferation, and exhibits both anti-anxiety and antidepressant properties. Anandamide, like all neurotransmitters, is metabolized quickly in the body. Cannabinoids which can bind to the same receptors as anandamide include cannabidiol (CBD), Δ-9-tetrahydrocannabinol (THC, the active ingredient in the prescription medication Marinol® (generic name dronabinol), 11-hydroxy-Δ-9-THC (a metaboloite of Δ-9-THC), cannabinol (CBN), Δ-8-THC, levonantradol, cannabivarin (CBDV), tetrahydrocannabivarin (THCV, a homologue of THC), cannabigerol (CBG), and acids and analogs thereof. It is now possible to synthesize many cannabinoids in the laboratory, eliminating the need to grow Cannabis for extraction of the naturally made compounds from its flowers.
Whole or crude marijuana (including marijuana oil or hemp oil) containing Δ-9-THC is regulated by the United States Drug Enforcement Administration (DEA) as a Schedule I Drug, ostensibly because it is a hallucinogen. The U.S. Food and Drug Administration (FDA) has not yet approved a drug product containing or derived from the whole Cannabis plant, even though Cannabis and Cannabis-derived products have been used by doctors to treat a number of medical conditions, such as AIDS wasting syndrome, epilepsy, neuropathic pain, treatment of spasticity associated with multiple sclerosis, and cancer and chemotherapy-induced nausea. Indeed, one of the most active areas of current research in the cannabinoid field is the study of the potential application of cannabinoids as therapeutic agents. Among these possible applications, cannabinoids have been known to exert palliative effects in cancer patients since the early 1970s. The best established of these effects is the inhibition of chemotherapy-induced nausea and vomiting.
Today, capsules of THC such as dronabinol (Marinol®, Syndros®) and synthetic cannabinoids such as nabilone (Cesamet®) are FDA-approved in the U.S., and also in several other countries for treating chemotherapy induced nausea and vomiting. In addition, medicinal use of Δ-9-THC is currently legal under state laws in many states, and THCV, a homologue of THC having a propyl (3-carbon) side chain instead of THC's pentyl (5-carbon) side chain, is currently being investigated for pharmaceutical purposes. THCV has been attracting a lot of attention because it is not regulated by the DEA and has potential in several medical applications. THCV has anti-anxiety, antioxidant, and neuroprotective properties, and has shown the ability to improve muscle control and reduce tremors in patients suffering from Alzheimer's and Parkinson's disease. THCV can also promote bone cell growth, regulate blood sugar levels, and suppress appetite.
Brain and spinal cord tumors are abnormal growths of tissue found inside the skull or the bony spinal column, which are the primary components of the central nervous system (CNS). The CNS is housed within rigid, bony quarters (i.e., the skull and spinal column), so any abnormal growth, whether benign or malignant, can place pressure on sensitive tissues and impair function. Tumors are classified according to the kind of cell from which the tumor seems to originate. Most primary malignant brain/CNS tumors are gliomas, caused by uncontrolled growth of glial cells which surround and support neurons. Gliomas can include (but are not limited to) astrocytoma, anaplastic astrocytoma, glioblastoma multiforme, oligodendroglioma, ependymoma, meningioma, lymphoma, schwannoma, and medulloblastoma. In a small number of individuals, primary tumors may result from specific genetic disease (e.g., neurofibromatosis, tuberous sclerosis) or from exposure to radiation or chemicals. The cause of most primary tumors remains a mystery.
Chemotherapy is a category of cancer treatment that uses strong drugs, typically administered orally or intravenously, to reduce or kill cancers and to prevent cancer cells from spreading to other parts of the body. While chemotherapy can be effective against cancer, it can also cause serious side effects, because the chemotherapy drugs which attack cancerous cells can also damage normal, healthy cells. Common chemotherapy-induced side effects include fever, chills, fatigue, insomnia, nausea/vomiting, sore mouth, diarrhea, constipation, loss of appetite leading to anorexia, pain or difficulty swallowing, swelling in the hands/feet, itching, shortness of breath, cough, muscle pain, and joint pain.
In general, cannabinoids can provide significant improvements in chemotherapy-induced side effects. Patients treated with THC and/or THCV have been shown to experience a higher quality of sleep and relaxation. The National Cancer Institute, an organization run by the U.S. Department of Health and Human Services, recognizes cannabinoids as an effective treatment for providing relief of a number of symptoms associated with cancer and chemotherapy treatments, including pain, nausea and vomiting, anxiety and loss of appetite. The American Cancer Society supports the need for more scientific research on cannabinoids for cancer patients, and recognizes the need for better and more effective therapies that can overcome the often debilitating side effects of cancer and its treatment. More specifically, one of the major cannabinoids found in Cannabis, cannabidiol (CBD), is effective at treating the more difficult to control symptoms of nausea, as well as preventing anticipatory nausea in chemotherapy patients. CB1 agonists such as tetrahydrocannabivarin (THCV) and tetrahydrocannabinol (Δ-9-THC) are also effective at reducing conditioned rejection and chemotherapy-induced nausea. Cannabinoids can also significantly reduce neuropathic pain where traditional treatment has been unsuccessful, and without adversely affecting the efficacy of the chemotherapy, and can also help prevent weight loss and a loss of appetite in chemotherapy patients. Research also suggests that Cannabis may reduce the swelling in the hands and feet that can often occur with chemotherapy treatment. Cannabinoids have been shown to have anti-inflammatory properties, to be helpful in pain management, and to reduce inflammatory pain.
Most chemotherapy treatment regimens typically used on cancers originating in other organs employ compounds or molecules that are too large to penetrate the blood-brain barrier (BBB). As a result, most current chemotherapy drugs can only be delivered to the brain via surgical implantation, or injection into the cerebrospinal fluid (CSF). The present invention envisions using cannabinoids such as THC, CBD or THCV to improve delivery of a chemotherapy compound across the BBB to the brain, and is based on the premise that the ready passage of cannabinoids across the BBB while complexed with a chemotherapy agent can be used for treating cancers in the brain. It would therefore be advantageous to attach a cannabinoid such as THC, CBD or THCV to a known chemotherapy agent for improved transport across the blood-brain barrier and therapeutic effect. It would also be useful to safely deliver chemotherapy drugs directly across the blood-brain barrier while also providing cannabinoids to treat some of the debilitating side effects of the chemotherapy.